FDA Approves Zelboraf (vemurafenib) for Erdheim-Chester Disease with BRAF V600 Mutation

In continuation of my update on Vemurafenib

The U.S. Food and Drug Administration today expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with Erdheim-Chester Disease (ECD), a rare cancer of the blood. Zelboraf is indicated to treat patients whose cancer cells have a specific genetic mutation known as BRAF V600. This is the first FDA-approved treatment for ECD.

“Today’s approval of Zelboraf for patients with ECD demonstrates how we can apply knowledge of the underlying genetic characteristics of certain malignancies to other cancers,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This product was first approved in 2011 to treat certain patients with melanoma that harbor the BRAF V600E mutation, and we are now bringing the therapy to patients with a rare cancer with no approved therapies.”

ECD is a slow-growing blood cancer that originates in the bone marrow. ECD causes an increased production of histiocytes, a type of white blood cell. Excess histiocytes can result in tumors infiltrating many organs and tissues throughout the body, including the heart, lungs, brain and others. ECD is estimated to affect 600 to 700 patients worldwide. Approximately 54 percent of patients with ECD have the BRAF V600 mutation. Patients with ECD have very limited life expectancies.

Zelboraf is a kinase inhibitor that works by blocking certain enzymes that promote cell growth.

The efficacy of Zelboraf for the treatment of ECD was studied in 22 patients with BRAF-V600-mutation positive ECD. The trial measured the percent of patients who experienced a complete or partial reduction in tumor size (overall response rate). In the trial, 11 patients (50 percent) experienced a partial response and 1 patient (4.5 percent) experienced a complete response.

Common side effects of Zelboraf in patients with ECD include joint pain (arthralgia); small, raised bumps (maculo-papular rash); hair loss (alopecia); fatigue; change in the heart’s electrical activity (prolonged QT interval) and skin growths (papilloma).

FDA Approves Vyzulta (latanoprostene bunod) Ophthalmic Solution for Open-Angle Glaucoma, Ocular Hypertension

Valeant Pharmaceuticals International, Inc.'s   announced that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%). Vyzulta, the first prostaglandin analog with one of its metabolites being nitric oxide (NO), is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.¹

"With today's approval of Vyzulta, our customers and their patients with glaucoma now have a new treatment option that can help provide consistent and sustained IOP lowering, the only modifiable risk factor that can help slow down the progression of the disease," said Joseph C. Papa, chairman and CEO, Valeant. "We expect to make this new advancement available for those who suffer with glaucoma before the end of the year."

Following topical administration, Vyzulta, a once daily monotherapy with a dual mechanism of action, works by metabolizing into two moieties, latanoprost acid, which primarily works within the uveoscleral pathway to increase aqueous humor outflow, and butanediol mononitrate, which releases NO to increase outflow through the trabecular meshwork and Schlemm's canal. The most common ocular adverse events include conjunctival hyperemia, eye irritation, eye pain and instillation site pain. Increased pigmentation of the iris and periorbital tissue and growth of eyelashes can occur. In glaucoma patients, damage to the trabecular meshwork, through which the majority of the aqueous humor passes, can lead to reduced drainage and as a result elevated IOP. Lowering IOP, even in patients with normal baseline levels, can delay, or even prevent damage to optic nerves, helping to reduce the risk of glaucomatous visual field loss.

"Vyzulta represents the first FDA-approved therapy developed through our proprietary NO-donating research platform," said Michele Garufi, chairman and CEO of Nicox. "We look forward to continuing to leverage our platform in the development of additional innovative ophthalmic compounds."

Preclinical studies have shown that NO plays a role in controlling IOP in normal eyes by increasing aqueous humor outflow through the trabecular meshwork and Schlemm's canal. Studies have also demonstrated that patients with glaucoma have reduced levels of NO signaling in their eyes, providing a rationale for the therapeutic value of NO-releasing molecules for patients with open-angle glaucoma or ocular hypertension.

"The safety and efficacy of Vyzulta has been well-established through multiple clinical studies, which have demonstrated positive results, including statistically significant differences in IOP lowering compared to timolol and latanoprost," said Robert N. Weinreb, M.D., chairman and distinguished professor of Ophthalmology and director, Hamilton Glaucoma Center at the University of California San Diego. "As one molecule with a dual mechanism of action, Vyzulta provides a new treatment option that works to reduce IOP by increasing the outflow through both the trabecular meshwork and the uveoscleral pathways."

Novel drug combination could enhance immunotherapy responses in patients with lung cancer

In continuation of my update on 5-azacytidine

Johns Hopkins Kimmel Cancer Center researchers and colleagues have identified a novel drug combination therapy that could prime nonsmall cell lung cancers to respond better to immunotherapy. These so-called epigenetic therapy drugs, used together, achieved robust anti-tumor responses in human cancer cell lines and mice.

During the study, published Nov. 30, 2017, in the journal Cell, a team of researchers led by graduate student Michael Topper; research associate Michelle Vaz, Ph.D.; and senior author Stephen B. Baylin, M.D., combined a demethylating drug called 5-azacytidine that chemically reignites some cancer suppressor genes' ability to operate, with one of three histone deacetylase inhibitor drugs (HDACis). The HDACis work against proteins called histone deacetylases that are involved in processes, such as cell copying and division, and can contribute to cancer development. The combination therapy triggered a chemical cascade that increased the attraction of immune cells to fight tumors and diminished the work of the cancer gene MYC. Based on these findings, investigators have launched a clinical trial of the combination therapy in patients with advanced, nonsmall cell lung cancer.

The development of therapeutic approaches for patients with lung cancer has been a critical medical need, says Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research at the Kimmel Cancer Center. While immune checkpoint therapy has been "a tremendous step forward, less than half of patients with lung cancer have benefited to date," he says.

"In our study, the two-drug epigenetic therapy combination worked exceedingly well, even before putting in the immune checkpoint inhibitors," Baylin says. "In animal models of lung cancer, the two agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors."

In a series of experiments, researchers studied the combination of 5-azacytidine with the HDACis entinostat, mocetinostat or givinostat in human cancer cell lines and in mouse models of nonsmall cell lung cancers. The treatments were found to alter the tumor microenvironment. In cancer cell lines, 5-azacytidine worked against the cancer gene MYC, causing down regulation of the entire MYC signaling program. Adding the HDACis further depleted MYC, and together the drugs subsequently caused actions that prevented cancer cell proliferation, simultaneously attracted more immune system T cells to the area of the tumor and activated these cells for tumor recognition.

 Entinostat,   Mocetinostat

 Givinostat

In mouse models, the strongest response was observed when using 5-azacytidine plus givinostat. In one mouse model with a mutant form of nonsmall cell lung cancer, this drug combination given for three months yielded prevention of benign, precursor tumors from becoming cancers and caused 60 percent reduction of overall area of benign tumor appearance in the lungs. By contrast, a group of mice with the same form of lung cancer that were given a mock treatment universally developed large, cancerous lesions in the lungs.

In a second model of mice with established, aggressive, nonsmall cell lung cancer, treatment with an alternating schedule of 5-azacytidine with givinostat and of 5-azacytidine with mocetinostat not only reduced the growth of established, rapidly growing primary tumors but also dramatically reduced metastatic occurrence.

Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia have started a phase I/Ib clinical trial to evaluate if giving mocetinostat with a 5-azacytidinelike drug called guadecitabine can boost immune checkpoint therapy responses in patients with advanced, nonsmall cell lung cancers. The trial is part of the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team and is funded by Merck through the Stand Up To Cancer (SU2C) Catalyst program, an initiative led by SU2C to bring innovative cancer treatments to patients quickly. Matthew Hellmann, M.D., an author on the paper, will lead this trial at Memorial Sloan Kettering, and Jarushka Naidoo, M.B.B.Ch., assistant professor of oncology, will lead at Johns Hopkins.

Ref : https://www.hopkinsmedicine.org/news/media/releases/2_drug_combination_may_boost_immunotherapy_responses_in_lung_cancer_patients

Novel drug combination could enhance immunotherapy responses in patients with lung cancer

FDA Approves Alecensa (alectinib) as First-Line Treatment for ALK-Positive Metastatic Non-Small Cell Lung Cancer

Genentech, a member of the Roche Group  announced that the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for Alecensa (alectinib) for the treatment of people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. The approval is based on results from the Phase III ALEX study, which showed Alecensa significantly reduced the risk of disease worsening or death (progression-free survival, PFS) by 47 percent (HR=0.53, 95 percent CI: 0.38, 0.73, p<0.0001) compared to crizotinib as assessed by independent review committee (IRC). Median PFS was 25.7 months (95 percent CI: 19.9, not estimable) for people who received Alecensa compared with 10.4 months (95 percent CI: 7.7, 14.6) for people who received crizotinib. The safety profile of Alecensa was consistent with that observed in previous studies.

The study also showed that Alecensa significantly reduced the risk of the cancer spreading to or growing in the brain or central nervous system (CNS) compared to crizotinib by 84 percent (HR=0.16, 95 percent CI: 0.10, 0.28, p<0.0001). This was based on a time to CNS progression analysis in which there was a lower risk of progression in the CNS as the first site of disease progression for people who received Alecensa (12 percent) compared to people who received crizotinib (45 percent).

“Our goal is to develop medicines that have the potential to significantly improve upon the standard of care,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “In our pivotal study, Alecensa significantly extended the time that people lived without their disease worsening compared to crizotinib and also showed a marked reduction in the risk of their cancer spreading to the brain.”

“ALK-positive lung cancer is often found in younger people, who tend to have more advanced disease at the time of diagnosis, and comes with a unique set of challenges," said Bonnie J. Addario, a lung cancer survivor and founder of the Bonnie J. Addario Lung Cancer Foundation (ALCF). “We applaud advancements in care, like the approval of Alecensa, which provides a new initial treatment option for people with this type of lung cancer.”

Alecensa received Breakthrough Therapy Designation from the FDA in September 2016 for the treatment of adults with advanced ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible. Results from the Phase III ALEX study were simultaneously presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine. Subsequently, Alecensa was recommended in the National Comprehensive Cancer Network (NCCN) guidelines as a treatment option for first-line ALK-positive metastatic NSCLC (Category 1, Preferred).

In addition to today’s approval, the FDA also converted Alecensa’s initial accelerated approval in December 2015 for the treatment of people with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib (second-line) to a full approval.

Drug that stimulates neuron pruning promotes goal-directed behavior in mice

A drug that stimulates neuron pruning can nudge mice away from habit-driven behaviors when combined with retraining, neuroscientists have found.

The results were published online on November 30 by Nature Communications.

The drug fasudil, approved in Japan for cerebral vasospasm and stroke, inhibits an enzyme that stabilizes cells' internal skeletons. The researchers suggest that fasudil or similar compounds could be effective tools for facilitating the treatment of drug abuse and preventing relapse.

A large fraction of the actions people perform each day come from habits, not from deliberate decision making. Going on auto-pilot can free up attention for new things, but it can also be detrimental, in the case of drug abuse and drug-seeking behavior, says lead author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

"Some habits are adaptive - for example, turning off a light when you exit a room - but others can be maladaptive, for example in the case of habitual drug use. We wanted to try to figure out a way to help 'break' habits, particularly those related to the highly-addictive drug cocaine," says Gourley.

Gourley and former graduate students Andrew Swanson, PhD and Lauren Depoy, PhD tested fasudil in situations where they had trained mice to poke their noses in two chambers, based on rewards of both food and cocaine. Then the researchers changed the rules of the game. The mice had to learn something new, in terms of where to poke their noses to get the reward.

In particular, the mice could now only get a reward from one chamber instead of both. Fasudil helped the mice adjust and display "goal-directed" behavior, rather than their previous habit-based behavior.

In addition, the researchers trained the mice to supply themselves a sweet cocaine solution. Then they changed the nature of that experience: the cocaine was paired with lithium chloride, which made the mice feel sick. Fasudil treatment nudged the mice to give themselves less cocaine afterwards, rather than continuing to respond habitually. The scientists envision this as modeling negative experiences associated with cocaine use in humans.

"Humans may seek treatment due to the negative consequences of cocaine abuse, but many people still relapse. We're trying to strengthen the goal of abstaining from drug taking," says Gourley.

The researchers conducted additional experiments that revealed that fasudil didn't make cocaine itself less pleasurable, but was specifically modifying the habit process. Also, fasudil did not affect other forms of decision making.

Un-learning of habits involves remodeling connections made by cells in the brain. In the mouse retraining experiments, the way that fasudil seems to work is that it promotes the pruning of dendritic spines. Dendritic spines are structures that help neurons communicate and embody the strength of connections between them.

Fasudil inhibits Rho kinase, which stabilizes F-actin, a major component of cells' internal skeletons. Thus, it loosens up cell structures. And in mice, fasudil appears to slightly reduce the density of dendritic spines in a region of the brain that is important for learning new behaviors.

"In this context, we imagine that fasudil is optimizing signal-to-noise, so to speak, allowing this brain region to efficiently guide decision making," says Gourley.

When fasudil is given to the mice a day after training, no changes in spine density are seen, indicating that it must be paired with new learning to have that effect.

Some caution is order, because overactive synaptic pruning is proposed to play roles in Alzheimer's disease and schizophrenia. In their paper, the authors conclude:

Pairing Rho kinase inhibitors with cognitive behavioral therapy in humans could be an effective pharmacological adjunct to reduce the rate of relapse... Given its favorable safety profile and our evidence that it can mitigate cocaine self-administration, fasudil is a strong candidate, with the caveats that we envision it administered as an adjunct to behavioral therapy and potentially during early phases of drug withdrawal.

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Drug that stimulates neuron pruning promotes goal-directed behavior in mice

FDA Approves Prevymis (letermovir) for Prevention of Cytomegalovirus (CMV) Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients

Merck & Co., Inc. ,  announced that the U.S. Food and Drug Administration (FDA) has approved Prevymis (letermovir) once-daily tablets for oral use and injection for intravenous infusion. Prevymis is indicated for prophylaxis (prevention) of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

CMV is a common and potentially serious viral infection in allogeneic HSCT recipients. CMV-seropositive patients who undergo an HSCT are at high risk for CMV reactivation. Any level of CMV infection is associated with increased mortality in HSCT patients.

In the pivotal Phase 3 clinical trial supporting approval, significantly fewer patients in the Prevymis group (38%, n=122/325) compared to the placebo group (61%, n=103/170) developed clinically significant CMV infection, discontinued treatment or had missing data through Week 24 post-HSCT [treatment difference: -23.5 (95% confidence interval -32.5 to -14.6), (p<0.0001)], the primary efficacy endpoint. All-cause mortality in patients receiving Prevymis was lower compared to placebo, 12% vs. 17%, respectively, at week 24 post-transplant. In this study, the incidence of bone marrow suppression in the Prevymis group was comparable to the placebo group. The median time to engraftment was 19 days in the Prevymis group and 18 days in the placebo group.

Prevymis is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. Prevymis is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

The concomitant use of Prevymis (letermovir) and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (Prevymis or concomitant drugs) or reduced therapeutic effect of Prevymis or the concomitant drug. Consider the potential for drug interactions prior to and during Prevymis therapy; review concomitant medications during Prevymis therapy; and monitor for adverse reactions associated with Prevymis and concomitant medications.

“Our findings demonstrate that letermovir is a significant and welcomed advance in the prevention of clinically significant CMV infection and lowers mortality in this highly vulnerable patient population,” said Dr. Francisco M. Marty, associate professor of medicine at Harvard Medical School and attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston.

The recommended dosage of Prevymis is 480 mg administered once daily, initiated as early as Day 0 and up to Day 28 post-transplantation (before or after engraftment), and continued through Day 100 post-transplantation. If Prevymis is co-administered with cyclosporine, the dosage of oral or intravenous Prevymis should be decreased to 240 mg once daily. Prevymis is available as 240 mg and 480 mg tablets, which may be administered with or without food. Prevymis is also available as 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over one hour.

“Prevymis is the first new medicine for CMV infection approved in the U.S. in 15 years,” said Dr. Roy Baynes, senior vice president, head of clinical development, and chief medical officer, Merck Research Laboratories. “Prevymis continues Merck’s longstanding tradition of bringing forward important new therapies to address serious infectious diseases. We are proud to add this breakthrough medicine to our existing offerings for physicians and patients.”

Prevymis is expected to be available in December. The list price (wholesaler acquisition cost) per day for Prevymis tablets is $195.00 and for Prevymis injection is $270.00. Wholesaler acquisition costs do not include discounts that may be paid on the product.

The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in patients receiving Prevymis than placebo (13% vs. 6%). The most common cardiac adverse events were tachycardia (reported in 4% Prevymis patients and 2% placebo patients) and atrial fibrillation (reported in 3% Prevymis patients and 1% placebo patients). These adverse events were reported as mild or moderate in severity. The rate of adverse events occurring in at least 10% of Prevymis-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% vs. 23%), diarrhea (26% vs. 24%), vomiting (19% vs. 14%), peripheral edema (14% vs. 9%), cough (14% vs. 10%), headache (14% vs. 9%), fatigue (13% vs. 11%), and abdominal pain (12% vs. 9%). The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of Prevymis patients and 1% of placebo patients). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one patient following the first infusion of IV Prevymis after switching from oral PREVYMIS, leading to treatment discontinuation.

Ref : https://www.drugs.com/history/prevymis.html

FDA Approves Prevymis (letermovir) for Prevention of Cytomegalovirus (CMV) Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients

FDA Approves New 10 mg Dosing for Xarelto (rivaroxaban) to Reduce the Continued Risk of Venous Thromboembolism (VTE)

In continuation of my update on rivaroxaban

Janssen Pharmaceuticals, Inc. announced  the U.S. Food and Drug Administration (FDA) approved the 10 mg once-daily dose of Xarelto (rivaroxaban) for reducing the continued risk for recurrent venous thromboembolism (VTE) after completing at least six months of initial anticoagulation therapy. This approval follows a FDA Priority Review and is based on data from EINSTEIN CHOICE, the only clinical study to find that a Factor Xa inhibitor, specifically Xarelto, demonstrates superior efficacy in reducing the continued risk of recurrent VTE and with major bleeding rates similar to aspirin.

VTE includes deep vein thrombosis (DVT), a blood clot in a deep vein (often the legs), and pulmonary embolism (PE), a clot that travels to the lung. It is the third most common cause of cardiovascular death worldwide, after heart attack and stroke.

"We believe the availability of the 10 mg Xarelto dose will change clinical practice and the management of VTE recurrence," said Paul Burton, MD, PhD, FACC, Vice President, Medical Affairs, Janssen. "The landmark EINSTEIN program results yet again demonstrate Xarelto is a safe and highly effective option, not only for the initial treatment of a VTE, but also for the continued prevention of a recurrent event."

With this approval, the Xarelto prescribing information provides instructions for physicians to begin treatment with Xarelto 15 mg, dosed twice daily, for the first 21 days after a VTE occurrence. On day 22 through at least day 180, the daily dose decreases to Xarelto 20 mg once daily. After at least 180 days (6 months), physicians can prescribe Xarelto 10 mg once daily in patients at continued risk for DVT and/or PE.

"If anticoagulation therapy is stopped, up to 20 percent of patients will have a recurrent VTE within three years. To prevent this, physicians have long debated how best to extend anticoagulant use beyond the initial treatment window," said Jeffrey Weitz, MD, FRCP(C), FACP, Professor, Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, and Executive Director, Thrombosis & Atherosclerosis Research Institute. "The FDA’s approval of the 10 mg dose of Xarelto for preventing recurrent VTE, along with clinical evidence confirming the superiority of Xarelto over aspirin for extended VTE prevention, means we can finally put this debate to rest."

The FDA’s approval of the Xarelto 10 mg once-daily dose was based on the EINSTEIN CHOICE study results. The EINSTEIN CHOICE study evaluated patients with VTE who were already treated with six to 12 months of initial anticoagulation therapy and then received Xarelto 10 mg once daily, Xarelto 20 mg once daily or aspirin 100 mg once daily for up to an additional 12 months of treatment. Patients taking either Xarelto dose had significantly fewer recurrent VTE compared to those taking aspirin. Specifically, Xarelto 10 mg reduced the risk of recurrent VTE by 74 percent and Xarelto 20 mg by 66 percent. All three treatment groups had low rates of major bleeding (0.4 percent with Xarelto 10 mg, 0.5 percent with Xarelto 20 mg, 0.3 percent with aspirin).

In September 2017, Janssen’s development partner Bayer announced the Committee for Medicinal Products for Human Use of the European Medicines Agency granted a positive opinion to update the Xarelto label to include the 10 mg once-daily dose in the European Union; the European Commission granted approval on October 19, 2017.

FDA Approves New 10 mg Dosing for Xarelto (rivaroxaban) to Reduce the Continued Risk of Venous Thromboembolism (VTE)

FDA Approves Auryxia (ferric citrate) Tablets as a Treatment for People with Iron Deficiency Anemia and Chronic Kidney Disease, Not on Dialysis

Keryx Biopharmaceuticals, Inc. (Nasdaq:KERX), a company focused on bringing innovative medicines to people with kidney disease, today announced that the U.S. Food and Drug Administration (FDA) has approved Auryxia for an additional indication. The approval is for the treatment of iron deficiency anemia in adults with chronic kidney disease (CKD), not on dialysis. Auryxia was originally approved in September 2014 for the control of serum phosphorus levels in people with chronic kidney disease who require dialysis.

With the new indication, millions of people living with chronic kidney disease have the potential to benefit from treatment with Auryxia. This medication is available today in pharmacies and covered broadly by Medicare Part D and commercial insurance providers in the United States.

“More than half of the approximate 30 million people in the United States living with chronic kidney disease are iron deficient, and yet, this is the only tablet that has been developed and approved specifically to address iron deficiency anemia in these patients, who are not on dialysis,” said Steven Fishbane, M.D., chief, division of kidney diseases and hypertension, department of medicine, Northwell Health in Great Neck, New York. “Starting today, physicians can prescribe an oral iron medicine to help people living with this condition, the majority of whom are not being optimally treated.”

Allergan Receives FDA Approval for Vraylar (cariprazine) in the Maintenance Treatment of Schizophrenia

In continuation of my update on Cariprazine

Allergan plc (NYSE: AGN)  announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for Vraylar (cariprazine) for the maintenance treatment of adults with schizophrenia. Vraylar is also approved in the U.S. in adults for the acute treatment of schizophrenia and acute treatment of manic or mixed episodes of bipolar I disorder.

"Schizophrenia is one of the most challenging mental health disorders to manage – particularly due to the complexity of patient symptoms, varying response to treatment and high rates of relapse," said Dr. Herbert Meltzer, Professor of Psychiatry and Behavioral Sciences at Northwestern Feinberg School of Medicine. "The goal of clinicians is to minimize relapses, which can cause significant personal distress, and can often have serious implications for a patient's health. The approval of Vraylar for the maintenance treatment of schizophrenia provides an important therapy for patients and physicians who are in need of long-term treatment options."

Without maintenance treatment, 60 – 70 percent of schizophrenia patients relapse within one year. Once a schizophrenia patient reaches the stable or maintenance phase of treatment, it is important for the physician to develop a long-term treatment management plan to minimize relapse risk, monitor for and reduce severity of side effects, and address residual symptoms where possible.²

The efficacy of Vraylar in the maintenance treatment of schizophrenia was based on an up to 72-week, multinational, double-blind, placebo-controlled, randomized withdrawal study in the prevention of relapse in adult patients with schizophrenia. The study included a 20-week open-label phase where patients with schizophrenia were treated with cariprazine 3, 6 or 9 mg per day. Patients who responded and met the stabilization criteria during the open-label period were then randomized either to continue their Vraylar dose (3, 6 or 9 mg per day) or be switched to placebo for up to 72 weeks or until a relapse occurred. The primary endpoint was time to relapse during the randomized, double blind phase.¹ The study demonstrated that Vraylar significantly delayed the time to relapse compared to placebo (P=0.0010). Relapse occurred in nearly twice as many placebo-treated patients (49.5%, n=49/99) as Vraylar-treated (29.7%, n=30/101) patients. The safety results were consistent with the profile observed to-date for Vraylar.

"The differences in how people with schizophrenia respond to treatment underscores the importance of having additional treatment options," said David Nicholson, Chief Research & Development Officer at Allergan. "We are pleased that the FDA has recognized the benefits of Vraylar for maintenance treatment of adults with schizophrenia. This approval demonstrates our continued investment in Vraylar, as well as our commitment to developing treatments that address unmet needs facing people living with mental illness."

FDA Approves Abilify MyCite (aripiprazole) Pill with Sensor to Digitally Track if Patients Have Ingested Their Medication

In continuation of my update on  aripiprazole 

The U.S. Food and Drug Administration today approved the first drug in the U.S. with a digital ingestion tracking system. Abilify MyCite (aripiprazole tablets with sensor) has an ingestible sensor embedded in the pill that records that the medication was taken. The product is approved for the treatment of schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder and for use as an add-on treatment for depression in adults.

The system works by sending a message from the pill’s sensor to a wearable patch. The patch transmits the information to a mobile application so that patients can track the ingestion of the medication on their smart phone. Patients can also permit their caregivers and physician to access the information through a web-based portal.

“Being able to track ingestion of medications prescribed for mental illness may be useful for some patients,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “The FDA supports the development and use of new technology in prescription drugs and is committed to working with companies to understand how technology might benefit patients and prescribers.”

It is important to note that Abilify MyCite’s prescribing information (labeling) notes that the ability of the product to improve patient compliance with their treatment regimen has not been shown. Abilify MyCite should not be used to track drug ingestion in “real-time” or during an emergency because detection may be delayed or may not occur.

Schizophrenia is a chronic, severe and disabling brain disorder. About 1 percent of Americans have this illness. Typically, symptoms are first seen in adults younger than 30 years of age. Symptoms of those with schizophrenia include hearing voices, believing other people are reading their minds or controlling their thoughts, and being suspicious or withdrawn. Bipolar disorder, also known as manic-depressive illness, is another brain disorder that causes unusual shifts in mood, energy, activity levels and the ability to carry out day-to-day tasks. The symptoms of bipolar disorder include alternating periods of depression and high or irritable mood, increased activity and restlessness, racing thoughts, talking fast, impulsive behavior and a decreased need for sleep.

Abilify MyCite contains a Boxed Warning alerting health care professionals that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Abilify MyCite is not approved to treat patients with dementia-related psychosis. The Boxed Warning also warns about an increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants. The safety and effectiveness of Abilify MyCite have not been established in pediatric patients. Patients should be monitored for worsening and emergence of suicidal thoughts and behaviors. Abilify MyCite must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

In the clinical trials for Abilify, the most common side effects reported by adults taking Abilify were nausea, vomiting, constipation, headache, dizziness, uncontrollable limb and body movements (akathisia), anxiety, insomnia, and restlessness. Skin irritation at the site of the MyCite patch placement may occur in some patients.

Prior to initial patient use of the product, the patient’s health care professional should facilitate use of the drug, patch and app to ensure the patient is capable and willing to use the system.

Abilify was first approved by the FDA in 2002 to treat schizophrenia. The ingestible sensor used in Abilify MyCite was first permitted for marketing by the FDA in 2012.

FDA Approves Abilify MyCite (aripiprazole) Pill with Sensor to Digitally Track if Patients Have Ingested Their Medication

Newly discovered drug-like compound may revolutionize treatment of autoimmune diseases

University of Colorado Boulder researchers have discovered a potent, drug-like compound that could someday revolutionize treatment of rheumatoid arthritis and other autoimmune diseases by inhibiting a protein instrumental in prompting the body to start attacking its own tissue.

"We have discovered a key to lock this protein in a resting state," said Hang Hubert Yin, a biochemistry professor in the BioFrontiers Institute and lead author of a paper, published today in Nature Chemical Biology, describing the discovery. "This could be paradigm shifting."

More than 23.5 million Americans suffer from autoimmune diseases like rheumatoid arthritis, scleroderma and lupus, in which an overzealous immune response leads to pain, inflammation, skin disorders and other chronic health problems.

Three of the top five selling drugs in the United States aim to ease their symptoms. But no cure exists, and treatments are expensive and come with side effects.

"Given the prevalence of these diseases, there is a big push for alternatives," Yin said.

For years, scientists have suspected that a protein called Toll-like receptor 8 (TLR8) plays a key role in the innate immune response. When it senses the presence of a virus or bacteria, it goes through a series of steps to transform from its passive to active state, triggering a cascade of inflammatory signals to fight off the foreign invader. But, as Yin explained, "it can be a double-edged sword" leading to disease when that response is excessive.

Because TLR8 has a unique molecular structure and is hidden inside the endosome -- an infinitesimal bubble inside the cell -- rather than on the cell's surface, it has proven an extremely difficult target for drug development.

"This is a long-sought-after target with very little success," Yin said.

But his study shows a drug-like molecule called CU-CPT8m binds to and inhibits TLR8 and exerts "potent anti-inflammatory effects" on the tissue of patients with arthritis, osteoarthritis and Still's disease, a rare autoimmune illness.

For the study, Yin and his co-authors used high-throughput screening to look through more than 14,000 small molecule compounds to determine whether they had the right chemical structure to bind to TLR8. They identified four that shared a similar structure.

Using that structure as a model, they chemically synthesized hundreds of novel compounds in an effort to find one that perfectly bound to and inhibited TLR8.

Previous efforts to target the protein have focused on shutting it down when it is in its active state. But the compound Yin discovered prevents it from activating while still in its passive state.

"Before, people were trying to close the open door to shut it down. We found the key to lock the door from the inside so it never opens," Yin said.

Much more research is necessary, but that could lead to treatments that strike at the root cause of autoimmune diseases, rather than just treating symptoms.

With help from CU's Technology Transfer Office, Yin has already filed a patent application and hopes to move on to animal studies and clinical trials within the next two years.

In the meantime, the new compound can serve as a first-of-its kind tool to understand exactly what TLR8 and the other nine toll-like receptors do in the body.

"Our study provides the first small molecule tool to shut this protein down so we can understand its pathogenesis," Yin said.

Ref : https://www.colorado.edu/today/2017/11/20/arthritis-autoimmune-disease-discovery-could-lead-new-treatments

Newly discovered drug-like compound may revolutionize treatment of autoimmune diseases

Multiple sclerosis drug can beat obstinate bacteria

In continuation of my update on glatiramer

Encountering bacteria with innocent names such as Pseudomonas aeruginosa and Enterobacteriaceae can lead to hospitalization and - in a worst-case scenario - can also be life-threatening. The bacteria, which cause infections such as pneumonia, frequently develop multi-resistance towards classic antibiotics.

Researchers from Aarhus University have discovered that a drug known as glatiramer acetate, which is normally used for treating the disease multiple sclerosis, has a hitherto unknown effect on obstinate bacteria.

Laboratory experiments have shown that the drug kills half of the Pseudomonas bacteria in specimens from patients with cystic fibrosis who are often exposed to the bacteria in the lungs.

The research results have recently been published in the scientific journal Scientific Reports.

The discovery is good news at a time where multi-resistant bacteria are a growing problem.

"We see great perspectives in the discovery because our data shows that the drug is effective against infections that occur because of what are known as Gram-negative bacteria. These bacteria form the basis of diseases such as pneumonia, cystitis and septic shock. Due to growing resistance, we are experiencing a decline in the number of effective treatments against them, and some of the medicaments which we otherwise know to be effective must be given in such high doses to be effective that they become toxic for the patients," explains Professor with special responsibilities (MSO) Thomas Vorup-Jensen from the Department of Biomedicine at Aarhus University.

According to a British survey commissioned by the British government, in 2050 resistant bacteria will all-in-all kill more people around the world than cancer. Neither the pharmaceutical industry or researchers have so far succeeded in developing new types of antibiotics that can beat the bacteria following classic strategies for the development of new medicines.

Multiple sclerosis drug can beat obstinate bacteria

Methotrexate drug holiday improves flu vaccine efficacy in rheumatoid arthritis patients

In continuation of my update on methotrexate

People with RA who stop taking methotrexate treatment for just two weeks after they have a seasonal flu shot can improve the vaccine's efficacy without increasing RA disease activity, according to new research findings presented this week at the 2017 ACR/ARHP Annual Meeting in San Diego.

Rheumatoid arthritis (RA) is a chronic disease that causes   pain,  stiffness,  welling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3million Americans have RA, and the disease typically affects women twice as often as men.

Methotrexate, a widely used immunosuppressant, can lower vaccine efficacy in people with RA. So researchers in Seoul, Republic of Korea, set out to investigate whether patients with RA could improve their response to influenza vaccinations by temporarily pausing methotrexate use for two weeks after their flu shot.

"RA patients are more susceptible to infections, including seasonal flu, due to their underlying abnormal immune function and the treatment-associated immune suppression," said Jin Kyun Park, MD, Assistant Professor of Medicine at Seoul National University Hospital, and a lead author of the study. "RA patients taking methotrexate are at even higher risk of infection and infection-related complications, so it's important that they be vaccinated against preventable infectious diseases. However, the immune suppression decreases vaccine response.

To overcome this shortcoming, our group has been working on a novel immunization protocol for RA patients to optimize vaccine response,  including increasing immunogenicity of flu vaccines."

In this prospective, multicenter, randomized, parallel-group trial conducted from October 2016 to January 2017, 316 RA patients who were taking a stable methotrexate dose were randomly assigned to two groups: 156 continued their regular methotrexate and 160 discontinued their dose for two weeks after receiving their flu shot. All participants were vaccinated with a seasonal, quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata and B-Victoria.

Methotrexate drug holiday improves flu vaccine efficacy in rheumatoid arthritis patients

FDA Approves Juluca, First Two-Drug Regimen for HIV Patients

In continuation of my updates on dolutegravir and rilpivirine,

The FDA has approved the first complete treatment regimen containing only two drugs to treat certain adults with human immunodeficiency virus type 1 (HIV-1) instead of the three or more drugs included in standard HIV treatment.

Juluca (dolutegravir/rilpivirine, ViiV Healthcare) is a fixed-dose tablet approved to treat adults with HIV-1 infections whose virus is currently suppressed (HIV-1 RNA less than 50 copies per mL) on a stable regimen for at least six months, with no history of treatment failure and no known substitutions associated with resistance to the individual components of the new combination. Dolutegravir 50 mg (ViiV Healthcare) is an integrase strand transfer inhibitor, and rilpivirine 25 mg (Janssen Therapeutics) is a non-nucleoside reverse transcriptase inhibitor.

 rilpivirine     Dolutegravir

 “Limiting the number of drugs in any HIV treatment regimen can help reduce toxicity for patients,” said Debra Birnkrant, MD, director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research.

HIV weakens a person’s immune system by destroying important cells that fight disease and infection. According to the Centers for Disease Control and Prevention, an estimated 1.1 million people in the United States are living with HIV, and the disease remains a significant cause of death for certain populations.

This FDA approval is based primarily on data from two pivotal phase 3 clinical trials, SWORD-12 and SWORD-2,2 which showed the two-drug regimen achieved non-inferior viral suppression (HIV-1 RNA less than 50 copies per mL) at 48 weeks compared with patients’ three- or four-drug current antiretroviral regimen (CAR) in both pooled and individual analyses of the SWORD-1 and SWORD-2 studies (dolutegravir/rilpivirine 486/513 [95%], CAR 485/511 [95%]; adjusted difference, –0.2%; 95% confidence interval, –3.0% to  2.5%, pooled analysis). Virological suppression rates were similar between treatment arms. Drug related adverse events and adverse events leading to withdrawal occurred in low frequencies in both arms of the study, but more frequently in the investigational arm.

The most common side effects in patients taking Juluca were diarrhea and headache. Serious side effects include skin rash and allergic reactions, liver problems, and depression or mood changes. Juluca should not be given with other anti-HIV drugs and may have drug interactions with other commonly used medications.

Ref : https://www.viivhealthcare.com/media/press-releases/2017/november/viiv-healthcare-announces-us-fda-approval-for-juluca.aspx

FDA Approves Juluca, First Two-Drug Regimen for HIV Patients

New findings on tolvaptan as autosomal dominant polycystic kidney disease treatment

 In continuation of my update on tolvaptan

A phase 3 trial studying the effects of tolvaptan has found that the drug slowed the rate of decline in kidney function in patients with the most common form of polycystic kidney disease, a condition with no cure. The results are published today in the New England Journal of Medicine.

Autosomal dominant polycystic kidney disease is an inheritedcondition that affects 1 in every 500 to 1,000 individuals in the U.S.This disease is found in all races and sexes.

Autosomal dominant polycystic kidney disease, which is the fourth most common cause of end-stage kidney disease, requires dialysis orkidney transplant.

The disease causes a slow but relentless growth of cysts that damage the kidneys. In addition to negatively affecting quality of life, thecondition also causes hypertension and painful complications. The cysts, which can damage kidneys with their size, can develop in other organs,especially the liver.

Approximately half of individuals with autosomal dominant polycystic kidney disease eventually will require dialysis or kidney transplant by age 60. The results of the trial demonstrated tolvaptan's ability to intervene in a way that slows kidney function decline in this population.

"This is the first treatment that targets a mechanism that directlycontributes to the development and growth of the kidney cysts inautosomal dominant polycystic kidney disease," says Vicente Torres, M.D., Ph.D., director of Mayo Clinic's Translational Polycystic Kidney Disease Center. "This in effect means it may delay the need for a kidney transplant or dialysis in patients with this disease."